Topoisomerase II poison and bis-dioxopiperazine derivative combination therapy

Abstract

The present invention relates to a method for selectively killing tumor or metastatic cells within a defined compartment of the organism of a large mammal, in particular a human, said method comprising administering to a mammal an effective tumor-or metastasis-killing amount of a topoisomerase II poison except doxorubicin, and protecting non-tumorous tissue of the mammal against the toxic action of the topoisomerase II poison by administration of a bis-dioxypiperazine compound. In particular, the invention relates to a pharmaceutical kit for selectively killing tumor or metastatic cells within the central nervous system in a large mammal, in particular a human, said kit comprising: a) a dosage unit of a bis-dioxypiperazine and a pharmaceutically acceptable carrier, and b) a dosage unit of topoisomerase II poisons except doxorubicin and a pharmaceutically acceptable carrier.

What is claimed is:  
     
       1. A method for selectively killing tumour cells within the central nervous system (CNS) compartment of a human, comprising administering to a human, outside said compartment, an effective tumour-cell killing amount of a topoisomerase II poison except doxorubicin, and protecting non-tumourous tissue outside said compartment of a human against the toxic action of the topoisomerase II poison by administration outside said compartment of a topoisomerase II poison-protective amount of a bis-dioxopiperazine compound, said topoisomerase II poison being antagonized by said bis-dioxopiperazine compound, and said compartment being one where the topoisomerase II poison is active and which is substantially inaccessible, as a result of the blood-brain barrier, to said bis-dioxopiperazine as administered, but accessible to said topoisomerase II poison as administered, 
       where said topoisomerase II poison is etoposide or teniposide and where said bis-dioxopiperazine is (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) or its (−)-isomer, where said combination of administrations is pharmaceutically acceptable  
       with the proviso that the tumour cell is not in a host infected with HIV. 
     
     
       2. A method according to claim  1  for selectively killing tumour or metastatic cells within the central nervous system of a human, comprising administering to a human an effective CNS-tumour- or metastasis-killing amount of a topoisomerase II poison except doxorubicin, and protecting non-CNS tissue of a human against the toxic action of the topoisomerase II poison by administration of a bis-dioxopiperazine compound, 
       the topoisomerase II poison and the bis-dioxopiperazine compound being selected and administered, with respect to their amounts, expressed in mg per m 2  of a human and with respect to the ratio between their amounts, in such a manner that in mice, the corresponding amounts (the conversion factor being so that 1 mg/kg in a human of a height of 180 cm and weighing 70 kg corresponding to a surface area of about 1.87 m 2 , corresponds to 3 mg/kg in a mouse) will conform to the following criteria:  
       i) in mice inoculated into the cerebrum with 15×10 4  Ehrlich's ascites tumour cells or 10×10 4  L1210 leukaemia cells in a volume of 30 μl of isotonic sodium chloride inoculated on day 0 into the temporal region, treatment i.p. on day 2 with the amount of the topoisomerase II poison and with simultaneous treatment with the amount of the bis-dioxopiperazine compound results in an increased life span of at least 125% compared to the increased life span in mice treated with topoisomerase II poison alone in an equitoxic dose (the equitoxic dose being calculated as the dose which in healthy mice results in a similar lethality as the combination); and/or  
       ii) in mice treated with the topoisomerase II poison alone and combined with the bis-dioxopiperazine compound respectively, the LD 10  of the combination is at least 25% higher than the LD 10  of the topoisomerase II poison alone.  
     
     
       3. A method for selectively killing tumour or metastatic cells within the intraperitoneal cavity or intrapleural cavity of a human, comprising administering to a human an effective tumour- or metastasis-killing amount of a topoisomerase II poison except doxorubicin and daunorubicin, and protecting non-tumourous tissue of a human against the toxic action of the topoisomerase II poison by administration of a bis-dioxopiperazine compound, the administration of topoisomerase II poison being performed locally to the cavity while the bis-dioxopiperazine compound is being administered systemically. 
     
     
       4. A method according to claim  1  wherein the topoisomerase II poison and the bis-dioxopiperazine compound are selected and administered to further conform to the following criterion: 
       iii) in mice inoculated i.p. with 15×10 6  Ehrlich's ascites tumour cells on day 0, treatment i.p. on day 4 with the amount of the topoisomerase II poison and with simultaneous treatment with the amount of the bis-dioxopiperazine compound results in an increased life span of at the most 200%, compared to the increased life span in mice treated with the topoisomerase II poison alone in an equitoxic dose (the equitoxic dose being defined as in claim  2 ).  
     
     
       5. A method according to claim  1 , wherein the topoisomerase II poison is administered in a dosage amount equivalent to at least 200 mg/m 2  of etoposide. 
     
     
       6. A method according to claim  1 , wherein the topoisomerase II poison is administered in a dosage amount equivalent to at least 2000 mg/m 2  of etoposide. 
     
     
       7. A method according to claim  1 , wherein the bis-dioxopiperazine compound is administered to a human in a dosage amount equivalent to at least 200 mg/m 2  of ICRF-187. 
     
     
       8. A method according to claim  1 , wherein the bis-dioxopiperazine compound is administered to a human in a dosage amount equivalent of at least 2000 mg/m 2  of ICRF-187. 
     
     
       9. A method according to claim  1 , wherein the ratio between the dosage amount of topoisomerase II poison and the dosage amount of the bis-dioxopiperazine to be administered is in the range of 1:6-6:1. 
     
     
       10. A method according to claim  1 , wherein the ratio between the dosage amount of topoisomerase II poison and the dosage amount of the bis-dioxypiperazine to be administered is in the range of 1:2-2:1, calculated on the weight of the active drugs. 
     
     
       11. A method according to claim  1 , wherein the topoisomerase II poison is administered in a dosage of between 3 and 15 g/m 2 . 
     
     
       12. A pharmaceutical kit comprising 
       a dosage unit of (a) a bis-dioxopiperazine and a pharmaceutically acceptable carrier, and  
       a dosage unit of (b) topoisomerase II poisons except doxorubicin and a pharmaceutically acceptable carrier,  
       said (a) and (b) being provided in amounts effective, in combination, for selectively killing tumor or metastatic cells 
       where said topoisomerase II poison is etoposide or teniposide and where said bis-dioxopiperazine is (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) or its (−)isomer.  
     
     
       13. A method according to claim  1 , wherein the topoisomerase II poison and the bis-dioxopiperazine are administered simultaneously. 
     
     
       14. A method according to claim  1 , wherein the bis-dioxopiperazine is administered prior to the administration of the topoisomerase II. 
     
     
       15. A method according to claim  14 , wherein the bis-dioxopiperazine is administered in the period of from 72 hours before the administration of the topoisomerase II poison to 24 hours after. 
     
     
       16. A method according to claim  1 , wherein the topoisomerase II poison and the bis-dioxopiperazine compound are selected and administered to conform to the following criterion: 
       i) in mice inoculated into the cerebrum with 15×10 4  Ehrlich's ascites tumour cells in a volume of 30 μl of isotonic sodium chloride inoculated on day 0 into the temporal region, treatment i.p. on day 2 with the amount of the topoisomerase II poison and with simultaneous treatment with the amount of the bis-dioxopiperazine compound results in an increased life span of at least 150%, compared to the increased life span in mice treated with topoisomerase II poison alone in an equitoxic dose as defined in claim  2 .  
     
     
       17. A method according to claim  1 , wherein the topoisomerase II poison and the bis-dioxopiperazine compound are selected and administered to conform to the following criterion: 
       ii) in mice treated with the topoisomerase II poison alone and combined with the bis-dioxopiperazine compound, respectively, the LD 10  of the combination is at least 50% higher than the LD 10  of the topoisomerase II poison alone.  
     
     
       18. A method according claim  1 , wherein the topoisomerase II poison and the bis-dioxopiperazine compound are selected and administered to conform to the following criterion: 
       iia) in mice treated with the topoisomerase II poison alone and combined with the bis-dioxopiperazine compound respectively, the LD 10  of the combination is at least 200% higher than the LD 10  of the topoisomerase II poison alone.  
     
     
       19. A method according to claim  1 , wherein the topoisomerase II poison is administered in a schedule where an administration is separated from the next administration by at least 2 days (48 hours). 
     
     
       20. A method according to claim  1 , wherein the topoisomerase II poison is administered in a schedule where an administration is separated from the next administration by at least 4 days. 
     
     
       21. A method according to claim  1 , wherein the topoisomerase II poison is administered in a schedule where each administration is separated from the next administration by at least 12 hours. 
     
     
       22. A method according to claim  21 , wherein each administration is separated from the next administration by from about 3 days to about 3 weeks. 
     
     
       23. A method according to claim  22 , wherein each administration is separated from the next administration by about 7 days. 
     
     
       24. A method according to claim  1 , wherein the topoisomerase II poison is etoposide. 
     
     
       25. A method according to claim  1 , wherein the topoisomerase II poison is teniposide (VM-26). 
     
     
       26. A method according to claim  1 , wherein the topoisomerase II poison is etoposide-phosphate. 
     
     
       27. The method of claim  1  in which the amount of the topoisomerase II poison administered is larger and more effective than the dose which would be an equitoxic dose in the absence of said bis-dioxopiperazine. 
     
     
       28. The method of claim  2  in which the amount of the topoisomerase II poison administered is larger and more effective than the dose which would be an equitoxic dose in the absence of said bis-dioxopiperazine. 
     
     
       29. The method of claim  1  in which the compartment is the peritoneal cavity. 
     
     
       30. The method of claim  1  in which the compartment is the pleural cavity. 
     
     
       31. The method of claim  1  where the poison and the compound are administered by infusion. 
     
     
       32. The method of claim  1  where the poison and the compound are administered intravenously. 
     
     
       33. The method of claim  1  where the poison and the compound are administered intraperitoneally. 
     
     
       34. The method of claim  1  in which the amount of the topoisomerase II poison administered is higher than what would be a pharmaceutically acceptable amount in the absence of the administration of said bis-dioxopiperazine. 
     
     
       35. The method of claim  1  in which the tumor cells belong to a primary cancer of the CNS. 
     
     
       36. The method of claim  1  in which the tumor cells belong to a CNS metastasis of a primary cancer located outside the CNS. 
     
     
       37. The method of claim  36  in which the metastasized cancer is a breast cancer. 
     
     
       38. The method of claim  36  in which the metastasized cancer is a testicular cancer. 
     
     
       39. The method of claim  36  in which the metastasized cancer is a small lung cancer. 
     
     
       40. The method of claim  36  in which the metastasized cancer is a lymphoma. 
     
     
       41. The method of claim  36  in which the metastasized cancer is a leukemia. 
     
     
       42. The method of claim  1  in which the amount of the bis-dioxopiperazine administered is such that if administered alone it would not have a statistically significant antitumor effect. 
     
     
       43. A method for selectively killing tumor cells in the peritoneal cavity compartment of a human, comprising 
       administering to said human, into said compartment, a tumor killing-amount of a topoisomerase II poison, said poison being etoposide or teniposide, and  
       administering to said human, outside said compartment, a topoisomerase II poison-antagonizing amount of a bis-dioxopiperazine compound, said compound being (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane or its (−)isomer, thereby protecting nontumor tissue outside said compartment from said topoisomerase II poison,  
       where said combination of administrations is pharmaceutically acceptable  
       with the proviso that the tumour cell is not in a host infected with HIV. 
     
     
       44. The method of claim  43  wherein the tumor cells are peritoneal metastases of an ovarian cancer or a mammary cancer. 
     
     
       45. The method of claim  1  in which both the topoisomerase II poison and the bis-dioxopiperazine are administered intravenously. 
     
     
       46. A method according to claim  1 , wherein the ratio between the dosage amount of topoisomerase II poison and the dosage amount of the bis-dioxopiperazine to be administered is in the range of 1.5:2-2:1.5 calculated on the weight of the active drugs. 
     
     
       47. A method according to claim  14 , wherein the bis-dioxopiperazine is administered in the period from 48 hours before to 12 hours after administration of the topoisomerase II poison. 
     
     
       48. A method according to claim  14 , wherein the bis-dioxopiperazine is administered in the period from 24 hours before to 6 hours after administration of the topoisomerase II poison. 
     
     
       49. A method according to claim  14 , wherein the bis-dioxopiperazine is administered in the period from 12 hours before to 3 hours after administration of the topoisomerase II poison. 
     
     
       50. A method according to claim  14 , wherein the bis-dioxopiperazine is administered in the period from 6 hours before to 1 hour after administration of the topoisomerase II poison. 
     
     
       51. A method according to claim  14 , wherein the bis-dioxopiperazine is administered in the period from 3 hours before to 1 hour after administration of the topoisomerase II poison. 
     
     
       52. A method according to claim  1 , wherein the topoisomerase II poison and the bis-dioxopiperazine are administered simultaneously. 
     
     
       53. A method according to claim  1  in which said topoisomerase II poison and said bis-dioxopiperazine are administered in a plurality of administrations. 
     
     
       54. The method of claim  53  in which the interval between administrations of the poison and the interval between administrations of the bis-dioxopiperazine are each four days.